Chronic pain affects over 100 million Americans. While opioids are recognized as the most effective drugs for the relief of pain, the US is now suffering from an epidemic of abuse, addiction and accidental overdose deaths resulting from prescription opioids. The goal of this proposal is develop a novel non-opioid analgesic drug devoid of addiction and abuse liabilities and to define its opioid-sparing effect. The combination of the non- opioid analgesic and opioid drug has the potential to lower opioid requirements, reduce side-effects, and decrease tolerance and abuse liabilities while maximizing pain relief. Transient receptor potential ankyrin 1 (TRPA1), is a critical ligand-gated ion channel on nociceptor nerve fiber endings, which is a validated target for novel analgesic drug for treating chronic pain. TRPA1 antagonists act directly on nociceptive nerve fiber endings to block initiation of action potentials by proalgesic substances and also have the capacity to inhibit peripheral sensitization. Algomedix has discovered and is developing a new orally delivered analgesic based on inhibition of the TRPA1 receptor-channel. In this proposal, we will assess a TRPA1 antagonist/opioid combination to determine if the combination synergistically enhances the analgesic efficacy of opioids and potentially limits the development of tolerance. Initial studies will demonstrate that newly synthesized potent and selective Algomedix TRPA1 antagonists with improved in vitro ADMET properties have analgesic efficacy in spinal neuron ligation (SNL) and chronic constriction injury models of neuropathic pain as well as opioid- sparing efficacy in these pain models. The lead compound, ALGX-XA42 strongly inhibits chronic pain in multiple animal models which include the SNL and chemotherapy-induced peripheral neuropathic pain without adverse behavioral effects. We therefore selected ALGX-XA42 for chemical optimization in our proposed Phase 2 SBIR project for analgesic drug development program. Utilizing the well-characterized structure- activity relationship for this series and metabolic identification data, we will synthesize a focused set of derivatives that specifically modify the metabolic hot-spot to achieve increased stability while retaining potency and other desirable drug-like properties. The top 10 modified leads meeting our matrix of ADMET selection criteria will be advanced for pharmacokinetic/pharmacodynamic testing. After defining efficacy in chronic pain, in vivo safety pharmacology and non-GLP toxicology in 2 species will be conducted. The milestone for the end of Phase II is the production of a therapeutic and backup clinical candidate. Completion of these studies will enable a go/no-go decision for final GLP IND-enabling studies. Our ultimate goal is to develop a novel therapeutic targeting the TRPA1 receptor-channel to treat chronic pain alone and as an opioid-sparing drug combination product.